Colorectal cancer (CRC) is a common, serious disease that clusters in families, such that individuals with an affected sibling are at almost 3-fold increased risk compared to those in the general population. Little, if any, of the observed familial clustering has yet been explained by shared environmental exposures. Known genetic syndromes such as hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP) are thought to account for less than 2% of cases. Unidentified susceptibility loci are probably important in much of the remaining non-syndromic familial colorectal cancer. We aim to identify novel CRC susceptibility loci collected via the Colon Cancer Cooperative Family Registry (Colon CFR). The Colon CFR is an NCI-supported consortium initiated in 1997 that has established a comprehensive collaborative infrastructure for interdisciplinary studies in CRC genetic epidemiology. Six cooperating registries have collected CRC tumor specimens, blood samples, and epidemiologic information from multiple-case families. Recruited CRC families from the Colon CFR, as well as from an additional site using identical protocols, who are not shown to carry HNPCC- or FAP-predisposing mutations will be included in a two-stage gene-mapping strategy. First, we will perform a genome-wide linkage analysis using 844 affected relative pairs in 499 families. Approximately 400 microsatellite markers will be genotyped and assessed for evidence of linkage to CRC using parametric and non-parametric methods; regions will be identified for follow-up. Second, individuals from 499 families will be genotyped using more densely-spaced microsatellite markers in genomic regions suggested by the initial scan. Parametric and non-parametric linkage methods will assess evidence for CRC linkage. Strengths of this effort include the use of an existing CRC family collection, a wealth of preliminary data (including screening for known mutations), and a successful collaborative history among investigators. A key future aim is to combine these families with those of other CRC linkage studies in the US and UK to amass an extensive resource with further increased power to understand CRC genetic susceptibility.